Abstract Multiple basic science and clinical lines of evidence suggest that traumatic brain injury (TBI) is characterized by several pathologies that combine to ultimately cause neurological and cognitive deficits in those that sustain head injury. Scientists and clinicians, alike, agree that efforts to rehabilitate those suffering from TBI have been curtailed by a lack of fundamental knowledge on how co-pathology contributes to outcome. Furthermore, to date no one has tested therapies aimed at poly-trauma (i.e., treating the multiple sequelae of events that occurs following head trauma). Therefore, we seek to investigate the contribution of both vascular and neuronal injury to poor outcome following TBI. The overall hypothesis is that vascular disruption and neuronal injury synergistically contribute to poor cognitive outcome following TBI. The specific research objectives of this proposal are to 1) characterize the neuronal and vascular response to TBI, 2) determine the contribution of vascular changes and/or neuronal injury on cognitive outcome and, 3) test the effect of improving both the vascular and neurologic deficits on neurological/behavioral outcome. This proposal ultimately tests new methods to improve behavioral outcome following TBI by improving blood flow to the brain and reducing secondary neuronal injury. In doing so, we aim to develop more effective strategies to rehabilitate those that have already sustained TBI. PUBLIC HEALTH RELEVANCE: Project Narrative Many of our men and women participating in The War on Terrorism have or will sustain head trauma. Efforts to develop strategies for ameliorating the deleterious effects of TBI have been curtailed by a lack of investigations into co-pathologies. Therefore, this proposal seeks to understand how hypoperfusion combined with cellular damage could lead to cognitive deficits. Furthermore, in doing so, this proposal aims to develop strategies to be given post TBI for improving outcome which will help to rehabilitate those how have already sustained an injury. Since both drug treatments are clinically relevant, we anticipate a quick transition from bench to bedside, thus maximizing our ability to improve the quality of life of those returning from Iraq and Afghanistan. Given the combined experience of all investigators in TBI research, it is expected that we will be able to deliver more effective means of treating post-TBI symptoms (e.g., neurologic and cognitive deficits) in order to more efficiently rehabilitate our service men and women to regain function and quality of life following head trauma.